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S64 SI THE TOXIC PATHOGEKTESIS OF BKONCHIAL ASTHMA
EUSTIS: THE TOXIC PATHOGENESIS OF BRONCHIAL ASTHMA 865

(2) A reflex asthma, caused by stimulation of the respiratory centre, are amins closely allied to putrescin and cadaverin. On putrefac-
through abnormalities in the various mucous membranes, as .well tion the several amino-acids split off carbon dioxide and form
as through a reflex stimulation of the respiratory centre through • their corresponding amins; so that we find a corresponding amin
the central organism itself, as in so-called .neurasthenia. (3) A to leucin, tyrosin, arginin, histidin, and the other amino-acids
toxic asthma, caused by the stimulation of the respiratory centre formed in pancreatic digestion of proteids. The physiological
through the toxic condition of the blood. action of the several amins have been excellently worked out by
Many other classifications are proposed, such as teeth asthma, Barger and Dale,12 and their results explain many of the clinical
. supposed to be caused by defective teeth; dyspeptic asthma; and symptoms observable in cases of intestinal toxemia, although their
sexual asthma, especially advocated by Sadger,9 a pupil of Freud, work was carried on with a view to obtaining the active principles
The various classifications will continue, to grow as long as we of ergot, adrenalin chloride; etc.
regard asthma as a distinct disease, instead- of as a symptom of Of the several amins, betaimidazolylethylamin, while it has
some other underlying constitutional condition. • a slight action on the blood pressure, has a specific action on
The few reports of postmortem sections of patients dying in unstriped muscle tissue, causing contraction of the uterus as well
attacks of asthma, which I have been able to find in the literature,10 as a contraction of the bronchioles, resulting in great dyspnea and
i are so widely at variance that no definite idea can be formed as death in the rabbit and guinea-pig, from complete occlusion of
i, to the pathology of this condition, further pointing to the fact air by the tonic spasm of the bronchioles. The isolation of this
i| that asthma should be classified as a symptom of an underlying amin and its physiological action was accidently discovered by
constitutional pathological condition, associated sometimes with ; Barger and Dale while investigating the action of ergot on the
epilepsy, sometimes with cardiac disease, and at times, probably, uterus. ATbout the same time ICutscher13 discovered a base in
with every disease known. extract of ergot which had the same A action on the bronchioles.
Hare11 lays a great deal of stress upon the 'toxic basis of asthma, Ackermann,14 we find, was able to obtain the base by the putre-
but his conclusions that it is brought on by "glycogenic distention faction of histidin, while Windhaus and Voigt,16 in 1907, were able
• of the liver," with resulting hypocarbonization of carbohydrates, is to obtain it synthetically from imidazolylproprionic acid, according
not based upon sound physiological facts, nor are his results in to the following steps:
accord with my experience. More likely the engorgement of the
liver of which he speaks allows the intestinal toxins to pass through Imidazolylpropionio acid. Histidin. Betaimidazolylethylamin.
into the general circulation without being synthesized, and their CH—NH CH—NH CH—NH
toxic action is thus manifested.
During the past summer and autumn, while working in Vienna CH J vCH . C CH
with Prof. Karl von Noorden and Prof, Richard ICraus, I decided
to attempt to prove or disprove our clinical deductions by animal
IV
i)H2. CH2. COOH;
. V s. CH NH2, COOH; CH2, CH2. NH2
\•
N
gentlemen experimentation, and I wish to take this means of thank-
ing these for their courtesy and assistance during my investigations Barger and Dale16 were later able to obtain this base from an
and for their free provision of material. extract of the intestinal mucosa of the ox, indicating that the
The hypothesis put forward to prove was: "If asthma is caused base is absorbed by this means from the intestinal canal. The
by intestinal toxemia a definite toxin exists, which, causes bronchial experiments carried on by Dale and Laidlaw17 .to determine its
spasm similar in action to muscarin, and this toxin originates in physiological action were made with the base separated by them
the intestinal canal." In seeking this specific toxin, I was led to from ergot and from the intestinal rnucosa, with the synthetic
investigate the amins formed by intestinal putrefaction of the substance of Windhaus and Voigt18 and with the base of Ackermann
several amino-acids of normal pancreatic digestion of proteids, as and Kutscher,19 as well as with some of the base obtained by the
I had long since satisfied myself by earlier chemical investigation putrefaction of histidin, the actions of which were all similar; so
and from the work of others, that the Charcot-jLeyden crystak—. that their results can safely be accepted as representing the physio-
logical action of betaimidazolylethylamin. '
' Zontralbl. f. Psychoanalyse, 1911, Hefto 5 and 6, p. 200.
"Meeting hold by tho Militararzlichen Gesellschaft, Berlin, 1886, p. 13] also see Bcrtot (HJTour. Phys., 1910, xli, 1 and 2, 19. " Zentrnlbl, f. Physiol., 1910, xxly, 103,
on Bronchial Asthma, its Pathology and Treatment, London, 1887; and Proceedings of tho .« Zeit. f. phys. Chein., 1910, Band Ixr, 504.
London Pathological Society, 1903. is Berioht des Deut. Geaellgohaft, 1907, xl, 3091.
14 Jour. Phys., 1910, xli, 494, No. 0. " Ibid., 31S, No. 5,
11 The Food Factor in Disease, London£l905, ,
>" Loo. oit, » Zeit. f. Biol,, 1910, Band liv, p, 387
866 THE TOXIC PATHOGENESIS OF BRONCHIAL ASTHMA EUSTIS: THE TOXIC PATHOGENESIS OF BRONCHIAL ASTHMA 867

Through the courtesy of Dr. Dale, I was able to obtain a large isolate the base by Kutscher's method from three specimens. of
supply of the base for experimental purposes, and in this preliminary feces, but was unsuccessful in twelve other specimens, suggesting
paper only a summary of the experimental work can be given, the that the presence of the base in intestinal contents will vary accord-
details of which will appear in a later article, after a few further ing tcTcfiet and probably also with varying intestinal flora.
experiments have been completed. I obtained the identical results Injections of the urine of asthmatics, as well as the urine of
as Dale and Laidlaw,20 namely, contraction of the uterus and normal guinearpigs and rabbits, cause the characteristic bronchial
bronchioles by intravenous injection, resulting in death from half a spasm and death, with the characteristic postmortem appearance
milligram in the guinea-pig, the animal dying in six minutes, with of the lungs above referred to (Fig. 2). The appearance of the lungs
violent inspiratory efforts, the heart continuing to beat long after and the symptoms of the animal are similar to those dying from an
respiration had ceased. At post mortem the lungs were found pale anaphylactic shock, recalling the opinion of Meltzer22 that asthma
and enormously distended and protruding from the thorax after sec- is a condition of anaphylaxis. The delayed coagulation of the
tion (Fig. 1). The spasm is so intense that when connected with a blood and the continuous fall of blood pressure, observable in
Meyer artificial respiration pump, no air can be forced in or drawn anaphylaxis is not found, however, after injections of betaimida-
out of the lungs, the organ remaining permanently distended, as zolylethylamin, although a lowered body temperature was uniformly
seen in anaphylaxis. In addition, I found that the same dose observed.

FIQ. 1.—Photograph of guinea-pig lungs after intravenous injection of 0.5 milligram of bctn-
imidazolylethylamin. Dark portions show normal lung tissue. ' Lighter portions arc emphy-
aematous.

administered into the trachea causes identical bronchial phenomena,


while subcutaneous and intraperitoneal injections are much less
toxic, suggesting that the action is entirely local on the unstriped
muscle fiber and that the subcutaneous tissues haye>a detoxicating
effect, Its action upon blood pressure and upon the uterus is not
pertinent to the present subject, and I would refer anyone interested Via. 2.—Photomicrograph of section of lung shown in Fig. 1. Note dilalntiou of mr vesicles,
in this particular point to the paper by Dale and Laidlaw.21 1 eyo-pieco and jf objective. X 87.
Attempts so far to isolate the base from the blood of asthmatics
have been unsuccessful, due to the many precipitations and filia- However, no one has as yet fully explained the phenomena of
tions; but experiments now in progress, I have reason to believe, anaphylactic shock, and it is possible that in injecting a foreign
will result in this being accomplished. However, I was able to serum a mixture of nitrogenous toxic bases is also injected, which
» Loo oit. "Loo oit. » Jour, Amer. Med. Assoc., 1910, Iv, 1021-1024.
868 COKLETT, COLE: DERMATITIS HIEMALIS CORLETT, COLE: DERMATITIS HIEMALIS 869

is ordinarily detoxicated, but which are not detoxicated by the equatorial zones and others are greatly modified by climatic
tissues on the second injection of serum owing to the previous influences.
injection having exhausted this hypothetical detoxicating sub- In 1874 Duhring1 called attention to a pruritus, common in
stance. From experiments, details of which will appear later, it winter in certain regions of North America, which he called prur-
appears that the normal human being, as well as the cat and dog, igo hiemalis. Hutchinson2 and Hyde3 have also emphasized the
have the power of detoxicating not only betaimidazolylethylainiu influence of climate in certain dermatoses.
but also the other toxic amins formed by intestinal putrefaction, The condition herein described first attracted attention in 1883,
while the asthmatic individual has apparently lost this power. since which time many cases have presented themselves for obser-
We are accustomed to notice urticaria as evidence of intestinal vation and study.
toxemia, while the eosinophilia in asthma and anaphylaxis are A report on the syndrome as observed in 14 cases was read
frequent accompaniments of intestinal toxemia. before the International Medical Congress in Rome, in 1894, by
In my paper before the Louisiana State Medical Society in 1909, one of the present writers, and later in the year it was presented
already referred to, I stated: "The fact that I have found evidence before the American Dermatological Association. In 1896 a second
of auto-intoxication in every case of asthma examined by me for report was read before the International Dermatological Congress
four years, leads me to believe that during the attack there is some in London. Again, in 1902, a more complete investigation of the
toxin in the blood which acts similarly to'the muscarin, or which condition was made, 9 additional cases being reported and care-
depresses the respiratory centre to such an extent that the reflex fully studied, both macroscopically and microscopically, especially
stimulation of an inflamed nasal mucosa results in stimulation of in regard to the possible parasitic causation of the disease, as well
the constrictor fibers of the vagus." as the relation it bears to an ordinary eczema.
I now submit the above facts as bearing out, in part, my original These studies may be summarized as follows: Dermatitis
contention, which I hope to be able to prove definitely in a short hiemalis is a cutaneous eruption having definite clinical symptoms,
time by the isolation of this specific amin from the blood of asth- following a fairly uniform course, and always associated with or
matics. limited to cold weather. It resembles eczema in that there is an
In closing, I wish to thank Dr. Maurice Couret, of the patho- inflammation, watery exudation, and some itching. Unlike eczema,
logical department of Tulane University, for his kindness in however, it more frequently is accompanied by smarting, burning,
taking the accompanying photographs. and tingling. It disappears during the summer months and reap-
pears the following autumn. The seat of predilection is the back
of the hands, wrists, and more rarely the fingers; very rarely the
feet, and never the trunk, arms, or thighs. Again, unlike eczema,
the lesions are circumscribed, well defined, often with elevated
A RECURRENT DISEASE OF THE SKIN ASSOCIATED WITH
edges, with a tendency to heal in the centre, All symptoms are
HIGH WINDS AND COLD WEATHER, FOR WHICH
aggravated by atmospheric changes, especially by. storms and
THE NAME DERMATITIS HIEMALIS HAS
sudden variation of temperature. The lesions are very resistant
BEEN PROPOSED, to treatment, although they disappear spontaneously at the
approach of summer or when the patient goes southward away from
BY WILLIAM THOMAS COKLETT, M.D., L.R.C.P. (LoND.), the lake region. Occupation or sex appear to have little to do with
PROFESSOR OF DEBMATOLOGY AND SYrHILOLOGY, WESTERN HESEKVE UNIVERSITY,
the condition. Careful examination for saprophytic organisms
has invariably given negative' results. From clinical studies the
AND
affection appears to be more closely allied to some of the erythemas
HAROLD NEWTON COLE, Pi-i.B., M.D., than to eczema, and may be similar to if not identical with the
HANNA RESEARCH FELLOW IN PATHOLOGY, WESTERN RESERVE UNIVERSITY, condition referred to by Jonathan Hutchinson4 as "some peculiar
eruptions allied to chilblains." Confirmatory is the suggestive
(From the Dermntological Clinic of the Lakeside Hospital, and the Pathological Laboratory
of Western Reserve University.) : -
bluish or purplish tint of the eruption that attacks the distal

THE skin from its exposed condition is more influenced by 1 Philadelphia Mod. Times, January 10, 1874.
1 Clinical Lectures, London, 1879, i, 362.
extraneous conditions, such as climate, etc., than are other organs ' Chicago Med. Jour, and Exam., 1885, 1, 187, and 1880, a, 11G.
of the body, Many diseases of the skin are limited to certain ' Loo. cit.

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